Cytokines promote Wnt signaling and inflammation and impair the normal differentiation and lipid accumulation in 3T3-L1 preadipocytes
Cytokines promote Wnt signaling and inflammation and impair the normal differentiation and lipid accumulation in 3T3-L1 preadipocytes
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DOI：
10.1074/jbc.m512077200
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发表时间：
2006-04-07
影响因子：
4.8
通讯作者：
Smith, U
中科院分区：
文献类型：
--
作者：
Gustafson, B;Smith, U
脂肪细胞增大的肥胖与脂肪组织中局部高浓度的白细胞介素-6（IL-6）和肿瘤坏死因子α（TNF α）相关。我们研究了这种炎症状态对3 T3-L1前脂肪细胞发育和分化为成熟脂肪细胞的影响。IL-6和TNF α均损害正常分化模式和脂质蓄积。然而，IL-6允许正常的早期诱导分化，抑制Wnt 10 b和Pref-1，而CCAAT/增强子结合蛋白α的表达，与过氧化物酶体增殖物激活受体γ相反，显着减少。TNF α也允许正常的早期分化诱导，而最终分化为脂肪细胞被完全阻止。然而，这两种细胞因子诱导的细胞的炎性表型，但具有不同的配置文件。值得注意的是，IL-6和TNF α都维持并增强了与低轴蛋白和高低密度脂蛋白受体相关蛋白（LRD）、Dishevelled和β-连环蛋白水平相关的经典Wnt信号传导。TNF α而非IL-6激活Wnt 10 b表达，而IL-6增加Dishevelled的表观磷酸化。因此，IL-6和TNF α都阻止前脂肪细胞正常发育为完全分化的脂肪细胞，相反，促进脂肪细胞的炎性表型。这些结果解释了为什么肥胖和糖尿病与局部和全身炎症、胰岛素抵抗和异位脂质积聚相关。
Obesity with enlarged fat cells is associated with high local concentrations of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) in the adipose tissue. We examined the effects of this inflammatory state on 3T3-L1 preadipocyte development and differentiation to mature adipose cells. Both IL-6 and TNF alpha impaired the normal differentiation pattern and lipid accumulation. However, IL-6 allowed a normal early induction of differentiation with inhibition of Wnt10b and Pref-1, whereas expression of CCAAT/ enhancer-binding protein alpha, in contrast to peroxisome proliferator-activated receptor gamma, was markedly reduced. TNF alpha also allowed a normal early induction of differentiation, whereas the terminal differentiation to adipose cells was completely prevented. However, both cytokines induced an inflammatory phenotype of the cells but with different profiles. Remarkably, both IL-6 and TNF alpha maintained and augmented the canonical Wnt signaling associated with low axin and high low density lipoprotein receptor-related protein (LRD), Dishevelled, and beta-catenin levels. TNF alpha, but not IL-6, activated Wnt10b expression, whereas IL-6 increased the apparent phosphorylation of Dishevelled. Thus, both IL-6 and TNF alpha prevent the normal development of preadipocytes to fully differentiated adipose cells and, instead, promote an inflammatory phenotype of the adipocytes. These results provide an explanation as to why obesity and diabetes are associated with both local and systemic inflammation, insulin resistance, and ectopic lipid accumulation.